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Definitions

• the present invention relates to a novel class of compounds which are activators of AMP-activated protein kinase (AMPK) (AMPK-activators), compositions comprising said compounds, methods of synthesis and uses for such compounds in treating various diseases mediated by AMPK, such as type 1 (Type I) diabetes, type 2 (Type II) diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, mitochondrial disorders, sarcopenia, obesity, hypertension, cerebral ischemia, cognitive defect, neurodegenerative diseases (including but not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease), neurological and mitochondrial disorders (including but not limited to schizophrenia, Friedrich's Ataxia, amyotrophic lateral sclerosis, multiple sclerosis), neuroinflammation, inflammatory pain, neuropathic pain, epilepsy, cardiac ischemia, virus infection (HIV, cytomegalovirus and hepatitis C) or cancer.
• AMPK AMP-activated protein kinase
• AMPK has been established as a sensor and regulator of cellular energy homeostasis (Hardie, D. G. and Hawley, S. A. AMP-activated protein kinase: the energy charge hypothesis revisited. Bioessays 23: 1112 (2001), Kemp, B. E. et. al. AMP-activated protein kinase, super metabolic regulator. Biochem. Soc. Transactions 31:162 (2003)). Allosteric activation of this kinase due to rising AMP levels occurs in states of cellular energy depletion. The resulting serine/threonine phosphorylation of target enzymes leads to an adaptation of cellular metabolism to the low energy state.
• AMPK activation induced changes are inhibition of ATP consuming processes and activation of ATP generating pathways, and therefore regeneration of ATP stores.
• AMPK substrates include acetyl-CoA-carboxylase (ACC) and HMG-CoA-reductase (Carling, D. et. al. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Letters 223:217 (1987)). Phosphorylation and therefore inhibition of ACC leads to a decrease in fatty acid synthesis (ATP-consuming) and at the same time to an increase in fatty acid oxidation (ATP-generating).
• ACC acetyl-CoA-carboxylase
• HMG-CoA-reductase HMG-CoA-reductase
• AMPK glycerol-3-phosphate acyltransferase
• AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target.
• malonyl-CoA decarboxylase (Saha, A. K. et. al. Activation of malonyl-CoA decarboxylase in rat skeletal muscle by contraction and the AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide-1-.beta.-D-ribofuranoside. J. Biol. Chem.
• AMPK adipocyte-derived hormone
• leptin leads to a stimulation of AMPK and therefore to an increase in fatty acid oxidation in skeletal muscle
• Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415: 339 (2002)).
• Adiponectin another adipocyte derived hormone leading to improved carbohydrate and lipid metabolism, has been demonstrated to stimulate AMPK in liver and skeletal muscle (Yamauchi, T. et. al.
• Adiponectin stimulates glucose utilization and fatty acid oxidation by activating AMP-activated protein kinase. Nature Medicine 8: 1288 (2002), Tomas, E. et. al. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. PNAS 99: 16309 (2002)).
• the activation of AMPK in these circumstances seems to be independent of increasing cellular AMP levels but rather due to phosphorylation by one or more yet to be identified upstream kinases.
• ZMP also acts as an AMP mimic in the regulation of other enzymes, and is therefore not a specific AMPK activator (Musi, N. and Goodyear, L. J. Targeting the AMP-activated protein kinase for the treatment of Type 2 diabetes. Current Drug Targets-Immune, Endocrine and Metabolic Disorders 2:119 (2002)).
• AMPK activator Musi, N. and Goodyear, L. J. Targeting the AMP-activated protein kinase for the treatment of Type 2 diabetes. Current Drug Targets-Immune, Endocrine and Metabolic Disorders 2:119 (2002).
• Several in vivo studies have demonstrated beneficial effects of both acute and chronic AICAR administration in rodent models of obesity and Type 2 diabetes (Bergeron, R. et. al.
• Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with Type 2 diabetes. Diabetes 51: 2074 (2002)), although it has to be determined to what extent its antidiabetic action relies on this activation. As with leptin and adiponectin, the stimulatory effect of metformin is indirect via a mild inhibition of mitochondrial respiratory chain complex 1 (Leverve X. M. et al. Mitochondrial metabolism and type-2 diabetes: a specific target of metformin. Diabetes Metab. 29: 6588 (2003)). In addition to pharmacologic intervention, several transgenic mouse models have been developed in the last years and initial results are becoming available.
• Stimulation of AMPK has been shown to stimulate production of ketone bodies from astrocytes (Blazquez, C. et. al. The AMP-activated protein kinase is involved in the regulation of ketone body production by astrocytes. J. Neurochem. 73: 1674 (1999)), and might therefore be a strategy to treat ischemic events in the brain. Stimulation of AMPK has been shown to improve cognition and neurodegenerative diseases in a mice model (Dagon Y. et al. Nutritional status, cognition, and survival: a new role for leptin and AMP kinase. J. Biol. Chem. 280:42142 (2005)).
• AMPK activation may be used to improve local circulatory systems.
• AMPK has also been described to directly affect PGC-1alpha activity through phosphorylation and then regulate mitochondria biogenesis (Jager S, et al. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci 104:12017 (2007)).
• AMPK activation can be then a way to treat mitochondrial disorders (e.g. sarcopenia and some mitochondrial rare diseases).
• mitochondrial disorders e.g. sarcopenia and some mitochondrial rare diseases.
• AMPK activation is proposed as a anti-viral therapy (Mankouri J. et al., Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase, Proc Natl Acad Sci 107: 11549 (2010)).
• AMPK activators may represent a strategy to protect the heart and other solid organs against cardiac ischemia as it has been demonstrated with A-769662 (Kim A. S. et al. A small molecule AMPK activator protects the heart against ischemia-reperfusion injury. J. Mol. Cell. Cardiology 51: 24 (2011)) or metformin (Yin M. et al. Metformin improves cardiac function in a non-diabetic rat model of 2 post-MI heart failure Am J Physiol Heart Circ Physiol 301: H459 (2011)).
• the present invention provides compounds of formula (I) or salts thereof:
• the invention provides compounds of formula (A)
• the present invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the present invention provides methods of treating type 1 diabetes, type 2 diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, mitochondrial disorders, sarcopenia, obesity, hypertension, cerebral ischemia, cognitive defect, neurodegenerative diseases (including but not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease), neurological and mitochondrial disorders (including but not limited to schizophrenia, Friedrich's Ataxia, amyotrophic lateral sclerosis, multiple sclerosis), neuroinflammation, inflammatory pain, neuropathic pain, epilepsy, cardiac ischemia, virus infection (HIV, cytomegalovirus or hepatitis C) or cancer comprising administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.
• a compound of formula (I) or a pharmaceutically acceptable salt thereof comprising administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.
• the present invention provides methods of treating type 1 diabetes, type 2 diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, mitochondrial disorders, sarcopenia, obesity, hypertension, cerebral ischemia, cognitive defect, Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, Friedrich's Ataxia, amyotrophic lateral sclerosis, multiple sclerosis, neuroinflammation, inflammatory pain, neuropathic pain, epilepsy, virus infection (HIV, cytomegalovirus or hepatitis C) or cancer comprising administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.
• HIV virus infection
• cytomegalovirus or hepatitis C virus infection
• the present invention provides methods of treating diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, obesity, hypertension, cerebral ischemia, cognitive defect and cancer comprising administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.
• the present invention provides methods of treating type 2 diabetes, obesity or dyslipidaemia comprising administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.
• the present invention provides methods of treating cancer comprising administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.
• the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in human or veterinary medical therapy.
• the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of type 1 diabetes, type 2 diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, mitochondrial disorders, sarcopenia, obesity, hypertension, cerebral ischemia, cognitive defect, neurodegenerative diseases (including but not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease), neurological and mitochondrial disorders (including but not limited to schizophrenia, Friedrich's Ataxia, amyotrophic lateral sclerosis, multiple sclerosis), neuroinflammation, inflammatory pain, neuropathic pain, epilepsy, cardiac ischemia, virus infection (HIV, cytomegalovirus or hepatitis C) or cancer.
• type 1 diabetes type 2 diabetes
• metabolic syndrome atherosclerosis
• dyslipidaemia mitochondrial disorders
• sarcopenia obesity
• hypertension cerebral ischemia
• cognitive defect including but not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease
• neurological and mitochondrial disorders including
• the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of type 1 diabetes, type 2 diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, mitochondrial disorders, sarcopenia, obesity, hypertension, cerebral ischemia, cognitive defect Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, Friedrich's Ataxia, amyotrophic lateral sclerosis, multiple sclerosis, neuroinflammation, inflammatory pain, neuropathic pain, epilepsy, virus infection (HIV, cytomegalovirus or hepatitis C) or cancer.
• HIV virus infection
• the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, obesity, hypertension, cerebral ischemia, cognitive defect or cancer.
• the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of type 2 diabetes, obesity or dyslipidaemia.
• the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
• the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of type 1 diabetes, type 2 diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, mitochondrial disorders, sarcopenia, obesity, hypertension, cerebral ischemia, cognitive defect, neurodegenerative diseases (including but not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease), neurological and mitochondrial disorders (including but not limited to schizophrenia, Friedrich's Ataxia, amyotrophic lateral sclerosis, multiple sclerosis), neuroinflammation, inflammatory pain, neuropathic pain, epilepsy, cardiac ischemia, virus infection (HIV, cytomegalovirus or hepatitis C) or cancer.
• type 1 diabetes type 2 diabetes
• metabolic syndrome atherosclerosis
• dyslipidaemia mitochondrial disorders
• sarcopenia obesity
• hypertension cerebral ischemia
• cognitive defect including but not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease
• the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of type 1 diabetes, type 2 diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, mitochondrial disorders, sarcopenia, obesity, hypertension, cerebral ischemia, cognitive defect Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, Friedrich's Ataxia, amyotrophic lateral sclerosis, multiple sclerosis, neuroinflammation, inflammatory pain, neuropathic pain, epilepsy, virus infection (HIV, cytomegalovirus or hepatitis C) or cancer.
• HIV virus infection
• the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, obesity, hypertension, cerebral ischemia, cognitive defect or cancer.
• the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of type 2 diabetes, obesity or dyslipidaemia.
• the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer.
• R 1 represents -(5 membered heteroaryl) optionally substituted by a group independently selected from —CH 3 , —OCH 3 , —OH, —CH 2 OH, —CF 3 , —OCF 3 , —CN, —CO 2 H, —CH 2 CO 2 H, —CONH 2 , —NH 2 or halogen.
• R 1 represents isoxazoyl, pyrrolyl, pyrazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1H-1,2,4-triazolyl or 1H-1,2,3-triazolyl optionally substituted by a group independently selected from —CH 3 , —OCH 3 , —OH, —CH 2 OH, —CF 3 , —OCF 3 , —CN, —CO 2 H, —CH 2 CO 2 H, —CONH 2 , —NH 2 and halogen.
• R 1 represents a 5-membered heteroaryl containing at least 1 N heteroatom optionally substituted with 1 or more groups selected from methyl, chloro, bromo, CO 2 H and methoxy.
• R 1 represents isoxazoyl, pyrrolyl, pyrazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1H-1,2,4-triazolyl or 1H-1,2,3-triazolyl optionally substituted by a group independently selected from —CH 3 , —OCH 3 , —CO 2 H— or halogen.
• R 1 represents a group selected from 3-methyl-5-isoxazoyl, 1-pyrazolyl, 3-methyl-1,2,5-oxadiazol-4-yl, 1H-1,2,4-triazol-1-yl, 3-carboxy-1-pyrrolyl, 1H-1,2,3-triazol-1-yl, 4-methyl-1-pyrazolyl, 4-carboxy-1-pyrazolyl, 1-methyl-4-pyrazolyl, 3-methyl-5-pyrazolyl, and 4-chloro-1-pyrazolyl.
• R 1 represents -(5 membered heteroaryl) optionally substituted by a —CH 3 group.
• R 1 represents
• R 1 represents O-phenyl optionally substituted with a group selected from methyl, methoxy, fluoro, ethoxy, and CO 2 H.
• R 1 represents O-phenyl optionally substituted with methoxy.
• R 3 represents
• R 3 represents
• R 3 represents
• R 3 represents
• alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms.
• —C 1-4 alkyl refers to a straight or branched “alkyl” containing at least 1, and at most 4, carbon atoms.
• alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, isobutyl, isopropyl and t-butyl.
• —C 6-10 aryl refers to an aromatic carbocyclic moiety containing 6 to 10 carbon ring-atoms.
• the definition includes both monocyclic and bicyclic ring systems and bicyclic structures at least a portion of which is aromatic and the other part is saturated, partially or fully unsaturated.
• aryl groups as used herein include, but are not limited to, naphthyl, indanyl, indenyl, azulenyl, azulanyl, phenyl and naphthyl; and more specifically phenyl.
• halogen refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo) atom.
• the term “-(5 membered heteroaryl)” refers to an aromatic cyclic group containing 5 ring-atoms 1, 2, 3 or 4 of which are hetero-atoms, at least 1 of which is N and the remaining 1, 2 or 3 are independently selected from nitrogen, oxygen and sulphur and the remaining ring-atoms are carbon.
• Examples of “-(5 membered heteroaryl)” include, but are not limited to isoxazolyl, pyrazolyl, oxadiazolyl, triazolyl, pyrrolyl, and thiazolyl, preferably isoxazolyl, pyrazolyl, 1H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, thiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl.
• substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
• one or more group refers to 1, 2 or 3 group, preferable 1 or 2 groups.
• pharmaceutically acceptable salt complexes are also included in the present invention.
• pharmaceutically acceptable salts of the compounds according to formula I may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Therefore, the present invention also covers the pharmaceutically acceptable salts of the compounds of formula (I).
• the term “pharmaceutically acceptable”, refers to salts, molecular entities and other ingredients of compositions that are generally physiologically tolerable and do not typically produce untoward reactions when administered to a subject (e.g. human).
• pharmaceutically acceptable also means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in a subject, and more particularly in humans.
• the term “subject” refers to an animal, in particular a mammal and more particularly to a human or a domestic animal or an animal serving as a model for a disease (e.g., mouse, monkey, etc.). In one aspect, the subject is a human.
• Salts of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion is pharmaceutically acceptable.
• salts having non-pharmaceutically acceptable counterions are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.
• Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include for example base addition salts e.g. ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine or for example acid addition salts formed from acids which form non-toxic salts e.g.
• base addition salts e.g. ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N
• solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
• solvents for the purpose of the invention may not interfere with the biological activity of the solute.
• suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
• the solvent used is a pharmaceutically acceptable solvent.
• the solvent used is water and the solvate may also be referred to as a hydrate.
• Solvates of compounds of formula (I) which are suitable for use in medicine are those wherein the solvent is pharmaceutically acceptable.
• solvates having non-pharmaceutically acceptable solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.
• the compounds of formula (I) may be in the form of pharmaceutically acceptable salts, solvates or solvates of salts. In a further aspect, the compounds of formula (I) may be in the form of pharmaceutically acceptable salts.
• the term “compounds of the invention” means the compounds according to formula (I) and pharmaceutically acceptable salts thereof.
• the term “a compound of the invention” means any one of the compounds of the invention as defined below.
• prodrug means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects.
• Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 and in D. Fleishner, S. Ramon and H. Barba “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19(2) 115-130.
• Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient.
• Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved in vivo yielding the parent compound.
• Prodrugs may include, for example, compounds of this invention wherein hydroxy or amine groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy or amine groups.
• representative examples of prodrugs include (but are not limited to) phosphonate, carbamate, acetate, formate and benzoate derivatives of hydroxy and amine functional groups of the compounds of formula (I).
• Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms).
• the individual stereoisomers (enantiomers and diastereomers) and mixtures or racemic mixtures thereof are included within the scope of the present invention.
• compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
• compounds of formula (I) may exist in the following tautomeric forms.
• racemic compounds of formula (I) may be optionally resolved into their individual enantiomers. Such resolutions may conveniently be accomplished by standard methods known in the art. For example, a racemic compound of formula (I) may be resolved by chiral preparative HPLC. An individual stereoisomer may also be prepared from a corresponding optically pure intermediate or by resolution, such as H.P.L.C. of the corresponding mixture using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding mixture with a suitable optically active acid or base, as appropriate.
• Compounds of the invention have been found to activate AMPK and may therefore be useful in the treatment of type 1 diabetes, type 2 diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, mitochondrial disorders, sarcopenia, obesity, hypertension, cerebral ischemia, cognitive defect, Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, Friedrich's Ataxia, amyotrophic lateral sclerosis, multiple sclerosis, neuroinflammation, inflammatory pain, neuropathic pain, epilepsy, virus infection (HIV, cytomegalovirus and hepatitis C) or cancer.
• HIV virus infection
• cytomegalovirus cytomegalovirus and hepatitis C
• Compounds of the invention have been found to activate AMPK and may therefore be useful in the treatment of diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, obesity, hypertension, cerebral ischemia, cognitive defect and cancer.
• the terms describing the indications used herein are classified in the Merck Manual of Diagnosis and Therapy, 17 th Edition and/or the International Classification of Diseases 10 th Edition (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention.
• the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy.
• the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease or a condition mediated by AMPK activation.
• the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating type 1 diabetes, type 2 diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, mitochondrial disorders, sarcopenia, obesity, hypertension, cerebral ischemia, cognitive defect, Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, Friedrich's Ataxia, amyotrophic lateral sclerosis, multiple sclerosis, neuroinflammation, inflammatory pain, neuropathic pain, epilepsy, virus infection (HIV, cytomegalovirus and hepatitis C) or cancer.
• HIV cytomegalovirus and hepatitis C
• the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, obesity, hypertension, cerebral ischemia, cognitive defect or cancer.
• the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating type 2 diabetes, obesity or dyslipidaemia.
• the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating type 2 diabetes, dyslipidaemia and cancer.
• the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating mitochondrial disorders or atherosclerosis.
• the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer.
• the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease or a condition mediated by AMPK activation.
• the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating type 1 diabetes, type 2 diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, mitochondrial disorders, sarcopenia, obesity, hypertension, cerebral ischemia, cognitive defect, Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, Friedrich's Ataxia, amyotrophic lateral sclerosis, multiple sclerosis, neuroinflammation, inflammatory pain, neuropathic pain, epilepsy, virus infection (HIV, cytomegalovirus and hepatitis C) or cancer.
• type 1 diabetes type 2 diabetes
• metabolic syndrome atherosclerosis
• dyslipidaemia mitochondrial disorders
• sarcopenia obesity
• hypertension cerebral ischemia
• cognitive defect Alzheimer's disease
• Parkinson's disease Huntington's disease
• schizophrenia Friedrich's Ataxia
• amyotrophic lateral sclerosis multiple sclerosis
• neuroinflammation inflammatory pain
• neuropathic pain epi
• the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, obesity, hypertension, cerebral ischemia, cognitive defect or cancer.
• the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating type 2 diabetes, obesity or dyslipidaemia.
• the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating type 2 diabetes, dyslipidaemia or cancer.
• the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating mitochondrial disorders or atherosclerosis.
• the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating cancer.
• the invention provides a method of treating a disease or a condition mediated by AMPK activation, which method comprises administering to a subject, for example a mammal, including human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the invention provides a method of treating type 1 diabetes, type 2 diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, mitochondrial disorders, sarcopenia, obesity, hypertension, cerebral ischemia, cognitive defect, Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, Friedrich's Ataxia, amyotrophic lateral sclerosis, multiple sclerosis, neuroinflammation, inflammatory pain, neuropathic pain, epilepsy, virus infection (HIV, cytomegalovirus and hepatitis C) or cancer, which method comprises administering to a subject, for example a mammal, including human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• a subject for example a mammal, including human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the invention provides a method of treating diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, obesity, hypertension, cerebral ischemia, cognitive defect and cancer, which method comprises administering to a subject, for example a mammal, including human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the invention provides a method of treating type 2 diabetes, obesity or dyslipidaemia, which method comprises administering to a subject, for example a mammal, including human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the invention provides a method of treating type 2 diabetes, dyslipidaemia or cancer, which method comprises administering to a subject, for example a mammal, including human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the invention provides a method of treating mitochondrial disorders or atherosclerosis, which method comprises administering to a subject, for example a mammal, including human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the invention provides a method of treating cancer, which method comprises administering to a subject, for example a mammal, including human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• treatment includes acute treatment or prophylaxis as well as the alleviation of established symptoms and/or retardation of progression of the disease, and may include the suppression of symptom recurrence in an asymptomatic patient.
• treatment includes acute treatment as well as the alleviation of established symptoms and/or retardation of progression of the disease, and may include the suppression of symptom recurrence in an asymptomatic patient.
• a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered as the bulk substance, it is preferable to present the active ingredient in a pharmaceutical formulation, for example, wherein the agent is in admixture with at least one pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
• the present invention also includes a pharmaceutical composition
• a pharmaceutical composition comprising a) a compound of formula (I) or a pharmaceutically acceptable salt thereof and b) one or more pharmaceutically acceptable carriers.
• pharmaceutically acceptable carrier refers to a diluent, excipient, and/or vehicle with which an active compound is administered.
• the pharmaceutical compositions of the invention may contain combinations of more than one carrier.
• Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions.
• Suitable pharmaceutical carriers or diluents are well known in the pharmaceutical art, and are described, for example, in “Remington's Pharmaceutical Sciences” by E. W. Martin, 18th Edition. The choice of pharmaceutical carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice.
• the pharmaceutical compositions may comprise as, in addition to, the carrier any suitable binder(s), lubricant(s), suspending agent(s) and/or coating agent(s).
• the carrier, diluent and/or excipient must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
• An “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
• compositions of the invention examples include, but are not limited to water, ethanol, propylene glycol and glycerine.
• binders for oral compositions useful herein include, but are not limited to, acacia; cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane resin, alginates, magnesium-aluminum silicate, polyethylene glycol or bentonite.
• acacia cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose
• gelatin glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane
• Examples of pharmaceutically acceptable lubricants useful in the compositions of the invention include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, and colloidal silicon dioxide.
• compositions of the invention examples include, but are not limited to, hydroxypropyl methylcellulose, ethyl cellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, polymers of metacrylic acid and its esters, and combinations thereof.
• Preservatives may be provided in the pharmaceutical composition.
• preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
• Antioxidants and suspending agents may be also used.
• the present invention relates to a pharmaceutical composition for the treatment of type 2 diabetes, dyslipidaemia or cancer comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the present invention relates to a pharmaceutical composition for the treatment of type 2 diabetes, obesity or dyslipidaemia comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the present invention further relates to a pharmaceutical composition
• a pharmaceutical composition comprising a) 10 to 2000 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and b) 0.1 to 2 g of one or more pharmaceutically acceptable carriers.
• the compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
• compositions of the invention may be formulated for administration by any suitable route, and include those in a form adapted for oral, parenteral, transdermal, inhalation, sublingual, topical, implant, nasal, enterally (or other mucosally) administration to mammals including humans.
• the pharmaceutical compositions may be formulated in conventional manner using one or more pharmaceutically acceptable carriers or excipients.
• the pharmaceutical composition is formulated for oral administration
• compositions may be in the form of tablets, capsules, powders, granules, lozenges, such as oral or sterile parenteral solutions or suspensions.
• Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
• the tablets may be coated according to methods well known in normal pharmaceutical practice.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
• suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
• fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred.
• the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
• the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
• the compounds of the invention may also, for example, be formulated as suppositories containing conventional suppository bases e.g. cocoa butter or other glyceride for use in human or veterinary medicine or as pessaries e.g., containing conventional pessary bases.
• conventional suppository bases e.g. cocoa butter or other glyceride for use in human or veterinary medicine
• pessaries e.g., containing conventional pessary bases.
• topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
• the compound of the present invention can be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e.g., a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), or a mixture thereof.
• a suitable propellant e.g., a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), or a mixture thereof.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• the pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g., using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant e.g. sorbitan trioleate.
• a lubricant e.g. sorbitan trioleate.
• Capsules and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.
• agents such as a local anaesthetic, preservative and buffering agent can be dissolved in the vehicle.
• the composition can be frozen after filling into the vial and the water removed under vacuum.
• the dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
• Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
• the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
• the compounds of the invention may be administered for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
• oral compositions are slow, delayed or positioned release (e.g., enteric especially colonic release) tablets or capsules.
• This release profile can be achieved, for example, by use of a coating resistant to conditions within the stomach but releasing the contents in the colon or other portion of the GI tract wherein a lesion or inflammation site has been identified.
• a delayed release can be achieved by a coating that is simply slow to disintegrate.
• the two (delayed and positioned release) profiles can be combined in a single formulation by choice of one or more appropriate coatings and other excipients. Such formulations constitute a further feature of the present invention.
• Suitable compositions for delayed or positioned release and/or enteric coated oral formulations include tablet formulations film coated with materials that are water resistant, pH sensitive, digested or emulsified by intestinal juices or sloughed off at a slow but regular rate when moistened.
• Suitable coating materials include, but are not limited to, hydroxypropyl methylcellulose, ethyl cellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, polymers of metacrylic acid and its esters, and combinations thereof.
• Plasticizers such as, but not limited to polyethylene glycol, dibutylphthalate, triacetin and castor oil may be used.
• a pigment may also be used to color the film.
• Suppositories are be prepared by using carriers like cocoa butter, suppository bases such as Suppocire C, and Suppocire NA50 (supplied by Gattefosse GmbH, D-Weil am Rhein, Germany) and other Suppocire type excipients obtained by interesterification of hydrogenated palm oil and palm kernel oil (C 8 -C 18 triglycerides), esterification of glycerol and specific fatty acids, or polyglycosylated glycerides, and whitepsol (hydrogenated plant oils derivatives with additives).
• Enemas are formulated by using the appropriate active compound according to the present invention and solvents or excipients for suspensions.
• Suspensions are produced by using micronized compounds, and appropriate vehicle containing suspension stabilizing agents, thickeners and emulsifiers like carboxymethylcellulose and salts thereof, polyacrylic acid and salts thereof, carboxyvinyl polymers and salts thereof, alginic acid and salts thereof, propylene glycol alginate, chitosan, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, N-vinylacetamide polymer, polyvinyl methacrylate, polyethylene glycol, pluronic, gelatin, methyl vinyl ether-maleic anhydride copolymer, soluble starch, pullulan and a copolymer of methyl acrylate and 2-ethylhexyl acrylate lecithin, lecithin derivatives, propylene glycol fatty acid esters, glycerin fatty acid esters
• materials may be incorporated into the matrix of the tablet e.g. hydroxypropyl methylcellulose, ethyl cellulose or polymers of acrylic and metacrylic acid esters. These latter materials may also be applied to tablets by compression coating.
• compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active ingredient, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient.
• the dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 1.5 to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.
• the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 59% of a compound of the invention.
• the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
• the compounds of formula (I) or pharmaceutically acceptable salt(s) thereof may also be used in combination with other therapeutic agents.
• the invention thus provides, in a further aspect, a combination comprising a) a compound of formula (I) or pharmaceutically acceptable salt thereof and b) one or more further therapeutically active agent(s).
• compositions comprising a combination as defined above together with one or more pharmaceutically acceptable carriers thereof represent a further aspect of the invention.
• Compounds of the invention may be administered in combination with other therapeutically active agents.
• Preferred therapeutic agents are selected from the list consisting of: insulin, bisguanidine, metformin, a DPP-IV inhibitor, sitagliptin, an inhibitor of cholesteryl ester transferase (CETP inhibitors), a HMG-CoA reductase inhibitor, a microsomal triglyceride transfer protein, a peroxisome proliferator-activated receptor activator (PPAR), a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, an ion-exchange resin, an antioxidant, an inhibitor of AcylCoA: cholesterol acyltransferase (ACAT inhibitor), a cannabinoid 1 antagonist, a bile acid sequestrant, a corticosteroid, a vitamin D3 derivative, a retinoid, an immunomodulator, an anti androgen, a kera
• each compound may differ from that when the compound is used alone.
• Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.
• compositions comprising a combination as defined above together with at least one pharmaceutically acceptable carrier and/or excipient comprise a further aspect of the invention.
• either the AMPK activator or the second therapeutically active agent may be administered first.
• the combination may be administered either in the same or different pharmaceutical composition.
• the two compounds When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
• compounds of formula (I) may be prepared according to reaction Scheme 1 by reacting compounds of formula (II) (wherein OR is a leaving group such as methoxy) in the presence of a base such as potassium tert-butoxide or potassium hexamethyldisilazane or lithium hexamethyldisilazane or sodium hexamethyldisilazane in a suitable solvent such as THF or DMSO (suitably at ⁇ 78° C. to 100° C.).
• a base such as potassium tert-butoxide or potassium hexamethyldisilazane or lithium hexamethyldisilazane or sodium hexamethyldisilazane
• a suitable solvent such as THF or DMSO (suitably at ⁇ 78° C. to 100° C.).
• Compounds of formula (I) may be alternatively prepared according to reaction Scheme 2 by reacting compounds of formula (X), with the appropriate R 3 -boron derivative (III) in the presence of an inorganic base such as cesium carbonate or sodium carbonate and a catalyst such as Pd(PPh 3 ) 4 in a suitable solvent such as a 1,4-dioxane/water mixture (suitably at 80 to 130° C., under microwave irradiation or classical heating).
• an inorganic base such as cesium carbonate or sodium carbonate
• a catalyst such as Pd(PPh 3 ) 4
• a suitable solvent such as a 1,4-dioxane/water mixture (suitably at 80 to 130° C., under microwave irradiation or classical heating).
• Compounds of formula (I) may be prepared according to reaction Scheme 6 by reacting compounds of formula (IV) (wherein OR is a leaving group such as methoxy) with compounds of formula (V) (R′: methyl or ethyl) in the presence of a base such as potassium hexamethyldisilazane in a suitable solvent such as THF (suitably at RT or 60° C.).
• Compounds of formula (II) may be prepared according to reaction Scheme 8 by reacting compounds of formula (IV) (wherein OR is a leaving group such as methoxy) with acetic acid derivatives (VI) in the presence of a coupling reagent such as HATU and a base such as triethylamine in a suitable solvent such as DCM (suitably at room temperature) or with acetyl chloride derivatives (VII) in the presence of a base such as triethylamine or pyridine in a suitable solvent such as DCM (suitably at 0° C.
• a coupling reagent such as HATU
• a base such as triethylamine
• a suitable solvent such as DCM (suitably at room temperature)
• acetyl chloride derivatives (VII) in the presence of a base such as triethylamine or pyridine in a suitable solvent such as DCM (suitably at 0° C.
• acetic acid derivatives (VI) in the presence of thionyl chloride in suitable solvent such as toluene or with acetic acid derivatives (VI) in the presence of oxalyl chloride in suitable solvent such as DCM or with acetic acid derivatives (VI) in the presence of POCl 3 or with acetic anhydride (suitably at room temperature).
• Compounds of formula (IVa) may be prepared according to reaction Scheme 9 by reacting compounds of formula (IV), wherein R 3 is 4-bromo-phenyl (formula (IVb)), with the appropriate R 6 -boron derivative (III) such as the appropriate boronic acid or appropriate borolane derivative in the presence of an inorganic base such as sodium carbonate or K 3 PO 4 and a catalyst such as Pd(PPh 3 ) 4 ) or PdCl 2 (dppf) in a suitable solvent such as 1,4-dioxane/water or THF/water mixture (suitably from 80 to 130° C.).
• R 3 is 4-bromo-phenyl (formula (IVb)
• R 6 -boron derivative (III) such as the appropriate boronic acid or appropriate borolane derivative
• an inorganic base such as sodium carbonate or K 3 PO 4
• a catalyst such as Pd(PPh 3 ) 4 ) or PdCl 2 (dppf)
• Compounds of formula (IV) may be prepared according to reaction Scheme 10 by reacting compounds of formula (IV), wherein R 3 is iodine (formula (IVc)), with the appropriate R 3 -boron derivative (111) such as the appropriate boronic acid or borolane derivative in the presence of an inorganic base such as sodium carbonate or cesium carbonate and a catalyst such as Pd(PPh 3 ) 4 in a suitable solvent such as a 1,4-dioxane/water mixture (suitably at 70 to 100° C.).
• Compounds of formula (IIIa) may be prepared according to reaction Scheme 12 by reacting compounds of formula (VIII) with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane in the presence of an inorganic base such as potassium acetate and a catalyst (such as PdCl 2 dppf.DCM) in a suitable solvent such as 1,4-dioxane (suitably at 100° C.).
• an inorganic base such as potassium acetate and a catalyst (such as PdCl 2 dppf.DCM)
• a suitable solvent such as 1,4-dioxane (suitably at 100° C.).
• Compounds of formula (V) may be prepared according to reaction Scheme 13 by reacting compounds of formula (IX) with ethyl 2-bromoacetate in the presence of an inorganic base such as potassium carbonate in a suitable solvent such as acetone (suitably at reflux) or in the presence of a base such as potassium tert-butoxide in a suitable solvent such as DMSO (suitably at RT).
• an inorganic base such as potassium carbonate in a suitable solvent such as acetone (suitably at reflux) or in the presence of a base such as potassium tert-butoxide in a suitable solvent such as DMSO (suitably at RT).
• the compounds of the invention may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, and more preferably 10 to 100 compounds.
• Libraries of compounds of the invention may be prepared by a combinatorial ‘split and mix’ approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
• a compound library comprising at least 2 compounds of the invention.
• Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, “Protective groups in organic synthesis” by T. W. Greene and P. G. M. Wuts (John Wiley & sons 1991) or “Protecting Groups” by P. J. Kocienski (Georg Thieme Verlag 1994).
• suitable amino protecting groups include acyl type protecting groups (e.g.
• aromatic urethane type protecting groups e.g. benzyloxycarbonyl (Cbz) and substituted Cbz
• aliphatic urethane protecting groups e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl or aralkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).
• the synthesis of the target compound is completed by removing any protecting groups, which are present in the penultimate intermediate using standard techniques, which are well-known to those skilled in the art.
• the final product is then purified, as necessary, using standard techniques such as silica gel chromatography, HPLC on silica gel, and the like or by recrystallization.
• MS mass spectra
• MS mass spectra
• MS mass spectra
• Analytical HPLC was conducted on a Waters XBridge column (2.5 ⁇ m 30 ⁇ 3 mm id) eluting with 0.01M ammonium acetate in water (solvent A) and 100% acetonitrile (solvent B) using the following elution gradient: 0 to 0.5 minutes, 5% B; 0.5 to 3.75 minutes, 5% B to 100% B; 3.75 to 4.5 minutes, 100% B; 4.5 to 5 minutes, 100% B to 5% B; 5 to 5.5 minutes, 5% B at a flowrate of 1.3 mL/min with a temperature of 40° C.
• MS mass spectra
• Intermediates 98 to 110 were prepared by methods analogous to that described for Intermediate 97.
• potassium tBuOK/DMSO was used instead of 1M KHMDS/THF.
• 1M LiHMDS/THF was used instead of 1M KHMDS/THF.
• Methyl 2-amino-4-chloro-5-iodobenzoate (Intermediate 2) (1 g, 3.21 mmol) and ethyl 2-(o-tolyloxy)acetate (Aldrich, 0.655 g, 3.37 mmol) were dissolved in THF (10 mL) and KHMDS 1M/THF (9.63 mL, 9.63 mmol) was added in one portion at room temperature under N 2 . The reaction mixture was stirred at room temperature for 1 h before quenched with MeOH and concentrated under reduced pressure. The residue was dissolved in 1N NaOH then extracted with Et 2 O.
• Intermediate 145 was prepared by methods analogous to that described for Intermediate 144.
• sodium carbonate was used instead of cesium carbonate as base.
• Examples 2 to 19 were prepared by methods analogous to that described for Example 1.
• Examples 21 to 26 were prepared by methods analogous to that described for Example 20.
• Examples 28 to 168 were prepared by methods analogous to that described for Example 27 (starting from boronic acid or borolane analogue). For Examples 32, 33, 34, 35, 36, 37, 38, 39, 40, 46, 47, 48, 49, 50, 52, 53, 54, 55, 56, 63, 66, 67, 68, 75, 76, 77, 78, 91, 93, 95, 96, 97, 98, 103, 104, 105, 117, 118, 120, 126, 127, 128, 129, 131, 132, 133, 135, 136, 137, 140, 141, 142, 143, 146, 148, 149, 157, 158, 162, 163, 164 and 166, sodium carbonate was used instead of cesium carbonate as base.
• the resulting material was taken up in water then acidified with 1N HCl. The solid was filtered then tritured in hot acetonitrile. The solid was filtered and dry under reduced pressure. The resulting solid was suspended in water (10 mL) and potassium hydroxide (101 mg, 1.796 mmol) was added. The reaction was stirred at 50° C. overnight.
• Examples 169 to 173 were prepared by a method analogous to that described for Example 168.
• Examples 175 to 181 were prepared by methods analogous to that described for Example 174.
• Examples 183 and 186 were prepared by methods analogous to that described for Example 182.
• Examples 188 to 190 were prepared by methods analogous to that described for Example 187.
• Example 192 was prepared by a method analogous to that described for Example 191.
• AMPK Human recombinant AMPK (Invitrogen #PV4673 & #PV4675) was used in a FRET assay format (Z'Lyte—Invitrogen). Assay conditions were as follow: ATP 100 ⁇ M, peptide (Invitrogen #PR8650) 2 ⁇ M, 1% final DMSO in Z'Lyte kinase buffer. Reaction was initiated by addition of 0.2-0.8 ng of AMPK and incubated for 1-hour @ 30° C. A further 1-hour incubation @ 30° C. with the development reagent (Invitrogen # PR5194) was performed.
• FRET signal was then measured and converted to “% peptide phosphorylation” according to Z'Lyte given calculation procedure. Evaluation of compounds was carried out using concentration-response curves. Final data were expressed in “% activation” calculating the ratio of “% peptide phosphorylation” between compound-condition and basal-condition. Alternatively pEC200 ( ⁇ Log(compound concentration leading to a 2-fold AMPK activity increase)) was produced through fitting of the concentration-response curves. All data were means of at least 2 independent experiments.
• some of the compounds of the invention give average pEC 50 values of ⁇ 6.0 when tested in this assay. In a further aspect, some of the compounds of the invention give average pEC 50 values of ⁇ 7.0 when tested in this assay. For instance, Example 42 was tested essentially as described above and gave an average pEC 50 value of 7.4.

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